The present invention is directed to the synthesis of a radioligand, labeled with a positron emitting radionuclide which is suitable for dynamic studies in humans using positron emission transaxial tomography. The radio-labeled ligand, [.sup.18 F]-N-methylspiroperidol, exhibits extremely high affinity for dopamine receptors and provides enhanced uptake and retention in the brain concomitant with reduced radiation burden. These quantities all combine to make [.sup.18 F]-N-methylspiroperidol a radioligand superior to known radioligands used for mapping dopamine receptors in normal and diseased states in the living brain. Additionally, a synthetic procedure is disclosed to prepare this novel radioligand.
Recent advances in the study of neuropsychiatric diseases link manifestations of a disease to chemical changes in the brain. For example, the dopamine neurotransmitter has been linked with both Parkison's disease and schizophrenia as a source for altered synaptic transmission at the biochemical level.
The development of positron emission transaxial tomography (PETT) has now made it possible to study the dopamine receptors in a living brain. Radioligands labeled with positron emitting radionuclides permit quantitative studies based on annihilation radiation produced during positron emission. The technique consists of intravenous injection of a radioligand or radiopharmaceutical and subsequent imaging of the distribution of the radioactive label based on detection of the annihilation radiation produced during positron emission. For additional information on PETT, see Brownell, et al., Science, Vol. 215, pp 619-626 (1982).
Radioligands which have proved useful for such studies are those with a high in vivo affinity for the dopamine receptors, including [.sup.11 C]pimozide, [.sup.18 F]haloperidol, [.sup.11 C]spiroperidol, [.sup.18 F]spiroperidol, [.sup.75 Br]-, [.sup.76 Br]-, or [.sup.77 Br]bromospiroperidol, N-[.sup.11 C]methylspiroperidol, [.sup.75 Br]- or [.sup.77 Br] brombenperidol, [.sup.75 Br]- or [.sup.77 Br]bromperidol, .sup.11 C-labeled derivatives of 2-amino-6, 7-dihydroxy-1,2,3,4-tetrahydronaphthalene, and [.sup.18 F]benperidol.
Each radioligand exhibits significantly different properties. For example, while the brain uptake of haloperidol is higher than spiroperidol or benperidol, it is characterized by rapid egress and relatively high nonspecific binding. Both [.sup.18 F]spiroperidol and [.sup.18 F]benperidol cross the blood brain barrier to a lesser extent than [.sup.18 F]haloperidol, but are retained to a greater degree by the striatum, a region of high dopamine receptor density. This retention is stereospecific; it is prevented by prior administration of the dopamine antagonist (+)-butaclamol, but not by its pharmacologically inactive enantiomer (-)-butaclamol. Furthermore, with [.sup.18 F]spiroperidol, no clearance from the striatal areas is observed for up to 8 hrs. after injection. However, one potential problem of using [.sup.18 F]spiroperidol in human PATT studies is the relatively low uptake into the brain (0.5-1.0% of the injected dose in baboons) and consequently, the potentially high radiation burden required to obtain sufficiently high counting rates for PETT studies in humans.
The compound of the present invention, no-carrier-added (NCA) [.sup.18 F]-N-methylspiroperidol exhibits greater uptake into the brain's dopamine receptor rich areas than [.sup.18 F]-spiroperidol.
N-Methylspiroperidol, described in U.S. Pat. No. 3,155,670, was recently labeled in the N-methyl position with carbon-11 and shown to have a similar pharmacological profile to spiroperidol, although no quantitative information was presented on its brain uptake (see Wagner, et al., Science. Vol. 221, pp. 1264-1266 (1983). In that report, N-[.sup.11 C]methylspiroperidol was used to image dopamine receptors in baboons and in humans using PETT. While N-[.sup.11 C]methylspiroperidol, as well as [.sup.11 C]spiroperidol, offers some interesting possibilities in terms of certain experimental protocols involving repeat injections at short time intervals in the same experimental subject, both compounds have the disadvantage that they cannot be followed for more than about 2 hrs. on PETT, because of the short half-life of carbon-11 (20.4 min.). This is a time course which does not allow accurate determination of some kinetic parameters and does not afford maximum definition of specific receptor binding.
The present NCA [.sup.18 F]-N-methylspiroperidol, however, exhibits characteristics more suitable for use in PETT analyses than the above-noted compounds. Example 2 shows that the time course of distribution of NCA [.sup.18 F]-N-methylspiroperidol is more rapid than for [.sup.18 F]spiroperidol. Examples 3 and 5 disclose that the distribution and stability of NCA [.sup.18 F]-N-methylspiroperidol is superior to that of [.sup.18 F]spiroperidol.
As a further aspect of the present invention, NCA [.sup.18 F]-N-methylspiroperidol is produced by a new synthetic route more accomodating to the short half-life of the .sup.18 F-label. Other methods of producing the spiroperidol class of reagents are too long and involved to make use of an attached radionuclide.